The present invention relates to the use of xenon for treating neurointoxications. More particularly, the present invention relates to a use of xenon in which the neurointoxication is caused by a neurotransmitter excess.
The uncontrolled release of neurotransmitters, particularly glutamate, noradrenalin and dopamine, is responsible for many acute and chronic intoxications of the brain. These are called neurointoxications or neuropoisonings. These neurotransmitters kill the affected neurons either by induction of apoptosis (controlled cell death) and/or secondarily by their metabolites, by forming oxygen radicals which in turn have toxic effects. An uncontrolled release of neurotransmitters which result in a strongly increased concentration of the neurotoxins in the affected tissue, can be due to various endogenous or exogenous causes. For example, an increased release of glutamate or dopamine may result in an acute craniocerebral trauma. An increase in the neurotransmitter release has also been observed as a response to oxygen deficiency in the brain, e.g. in the case of apoplexy (ischemia) or in the case of other hypoxias, particularly during childbirth. Drug abuse represents another cause of impaired neurotransmitter release. In certain forms of schizophrenia, stress-induced relapses back into schizophrenia (acute episodes) are also accompanied by increased neurotransmitter release. Finally, a chronic shift of neurotransmitter balance, particularly of dopamine balance, has also been observed in various regions of the brain in the case of Parkinson""s disease. Increased dopamine release and subsequent formation of free radicals occur in that case as well. Various investigations made with cell cultures and experimental animals have proven the release of neurotransmitters, particularly as a result of oxygen deficiency.
For example, it can be shown that in rats into which the dopamine neurotoxin 6-hydroxy-dopamine was infused unilaterally into the substantia nigra, which resulted in a unilateral depletion of dopamine in the ipsilateral striatum, an experimentally induced ischemia in the regions of dopamine depletion led to damage which was less than that in other regions of the brain. These results suggest that dopamine plays a part in ischemia-induced striatal cell death (Clemens and phebus, Life Science, Vol. 42, p. 707 et seq., 1988).
It can also be shown that dopamine is released in great amounts from the striatum during cerebral ischemia (Kahn et al., Anest.-Analg., Vol. 80, p. 1116 et seq., 1995).
The release of neurotransmitters during cerebral ischemia was investigated in detail and seems to play a key role for excitotoxic neural death. For example, Kondoh et al., Neurosurgery, Vol. 35, p. 278 et seq., 1994, showed that changes in the neurotransmitter release and metabolization can reflect changes in the cellular metabolism during ischemia. The increase in the extracellular dopamine concentration in the striatum of experimental animals in which experimental apoplexies were induced, is well documented.
The contribution of excess dopamine to neuronal damage can be derived from the ability of dopamine antagonists to obtain protection of the neurons in ischemia models (Werling et al., Brain Research, Vol. 606, p. 99 et seq., 1993). In a cell culture, dopamine primarily causes apoptosis of striatal neurons, without damaging the cells by a negative effect on the oxidative phosphorylation the (ATP/ADP ratio remains unchanged). However, if its effect is combined with a minimum inhibition of mitochondrial functions, the neurotoxic effect of dopamine will be increased significantly (McLaughlin et al., Journal of Neurochemistry, Vol. 70, p. 2406 et seq., 1998).
In addition to the direct hypoxic toxicity on neurons, the stress induced by oxygen deficiency, particularly during a birth, effects an increased dopamine release, which results in a negative conditioning of the brain for dopaminergic regulations. This means that even children who seem to survive a hypoxic birth phase uninjured, have a tendency towards convulsions and epileptic conditions when they are older.
Another cause of a disturbed neurotransmitter release is represented by drug abuse. In particular, if drugs such as designer drugs (e.g. ecstasy, etc.) or heroin are consumed, and amphetamines are overdosed, the persons will show signs of intoxication and often spasmophilia, which is based on an increased neurotransmitter release.
The causes of schizophrenia are also due to a complex impairment of the neurotransmitter regulation. Schizophrenia patients are often asymptomatic over a prolonged period of time, but they have a tendency towards spontaneous schizophrenia attacks which are obviously triggered by a stress-induced dopamine release, even in minor stress situations. Here, one speaks of catatonic schizophrenia. Further neuropsychiatric diseases which are based on an increased neurotransmitter release are depressions and Gilles de la Tourette syndrome (xe2x80x9cmaladie de ticsxe2x80x9d, xe2x80x9cTics impulsifxe2x80x9d).
Finally, one cause of Parkinson""s disease is presently believed to be in dopamine modulation and in dopamine metabolism. In Parkinson""s disease, dopaminergic neurons in the striatum are especially damaged. References exist to the effect that Parkinson""s disease is caused by a dopamine excess in the affected region of the posterolateral hypothalamus and the substantia nigra. Many neurons which have lost their functionality but not their vitality are found in this region. These neurons, referred to as xe2x80x9corphan neurons,xe2x80x9d continuously release neurotransmitter amounts having pathologic effects.
With the exception of Parkinson""s disease, where dopa precursors are used as preparations, basically of schizophrenia, no therapeutic approaches presently exist which focus on a reduction of the dopamine concentration in the environment of endangered cells.
Therefore, there is a demand for a preparation which reduces or prevents the damaging effects of uncontrolled neurotransmitter release, e.g. of dopamine, glutamate or noradrenalin, from neurons. It is therefore an object of the present invention to provide such a preparation which can be of use in the above-mentioned, as well as in other fields of application.
In accordance with the present invention, these and other objects have now been realized by the discovery of a method for treating a mammal for neurointoxication comprising treating the mammal with a xenon-containing gas. Preferably, the xenon-containing gas comprises a mixture of gases.
In accordance with one embodiment of the method of the present invention, the neurointoxication is caused by an excess of neurotransmitter in the mammal.
In accordance with another embodiment of the method of the present invention, treating of the mammal with the xenon-containing gas comprises reducing the release of neurotransmitters in the mammal. Preferably, the neurotransmitters are dopamine, glutamate and/or noradrenalin.
In accordance with another embodiment of the method of the present invention, the neurointoxication is caused by apoplexy. In other embodiments, the neurointoxication is caused by drug abuse, oxygen deficiency during birth, a craniocerebral trauma, loss of hearing, or migraine.
In accordance with another embodiment of the method of the present invention, the neurointoxication is correlated with a condition such as Parkinson""s disease, schizophrenia, or Gilles de la Tourette syndrome.
In accordance with another embodiment of the method of the present invention, the treating of the mammal with the xenon-containing gas comprises using a cardiopulmonary bypass machine.
In accordance with another embodiment of the method of the present invention, the xenon-containing gas comprises an administered preparation containing from 5 to 90% by volume of the xenon.
In accordance with another embodiment of the method of the present invention, the xenon-containing gas comprises an administered preparation containing from 5 to 30% by volume of the xenon.
In accordance with another embodiment of the method of the present invention, the xenon-containing gas comprises an administered preparation containing a gas such as oxygen, nitrogen or air. Preferably, the xenon-containing gas comprises oxygen, and the ratio of the xenon to the oxygen is from about 80 to 20% by volume.
In accordance with another aspect of the present invention, a treatment method has been discovered comprising using xenon as a neuroprotectant.
In accordance with yet another aspect of the present invention, a method of providing neuroprotection in a mammal has been discovered, the method comprising administering to the mammal a therapeutically effective amount of xenon. Preferably, the method includes administering the xenon in combination with a compound such as a pharmaceutically acceptable carrier, diluent and/or excipient.
In accordance with another embodiment of this method of the present invention, the method includes treating the mammal for a condition associated with NMDA receptor activity.
In accordance with another embodiment of this method of the present invention, the method includes treating the mammal for a condition associated with NMDA receptor activation.
In accordance with another embodiment of this method of the present invention, the xenon reduces the level of activation of the NMDA receptor.
In accordance with yet another aspect of the present invention, a process has been provided for the preparation of a pharmaceutical composition suitable for neuroprotection, the process comprising adding xenon to a component such as a pharmaceutically acceptable carrier, excipient and/or diluent, and using the xenon as a neuroprotectant.
In accordance with the present invention, it has been found that the noble gas xenon surprisingly now reversibly suppresses the release of neurotransmitters, particularly dopamine and glutamate. This unexpected discovery has thus created the possibility of producing preparations for treating cell damage and diseases, respectively, which are caused by an increased neurotransmitter release, and particularly dopamine release or glutamate release.
Correspondingly, the present invention generally relates to the use of xenon for treating neurointoxications, and on the production of a preparation containing xenon for treating neurointoxications, respectively. The present invention also relates to the preparations per se and to a method of producing same. Such neurointoxications particularly concern an excess of neurotransmitter. The present invention is particularly based on the insight that xenon reduces the release of dopamine and/or glutamate.